tbuckley/cabot-search huggingface dataset:
Abstract 2342: Quinolinate promotes alternatively activated macrophage-induced immune tolerance in glioblastoma through the NMDA/PPARy signaling axis
Authors: Pravin Kesarwani, Shiva Kant, Antony Prabhu, Katie L. Buelow, C. Ryan Miller, Prakash Chinnaiyan
Journal: Cancer Research (2022)

Abstract There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. An overwhelming majority of this work has focused on the upstream metabolism of tryptophan, however, this has not resulted in clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and went on to demonstrate its critical role in promoting immune tolerance. QA acts as a “metabolic checkpoint” in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling, resulting in amplification of immune suppressive macrophages. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer the scientific community an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing new immune modulatory agents to further clinical gains in these otherwise incurable diseases. Citation Format: Pravin Kesarwani, Shiva Kant, Antony Prabhu, Katie L. Buelow, C. Ryan Miller, Prakash Chinnaiyan. Quinolinate promotes alternatively activated macrophage-induced immune tolerance in glioblastoma through the NMDA/PPARy signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2342.
Abstract 2124: ATRA mediated inhibition of myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in murine models of LKB1-deficient non-small cell lung cancer
Authors: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen W. Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Camelia Dumitras, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Bin Liu, Steven M. Dubinett
Journal: Cancer Research (2022)

Abstract Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of patients harbor somatic mutations in both Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes. LKB1 loss has been identified as a driver of primary resistance to ICI therapy. Tumors from patients that possess these mutations are characterized by an increase in the population of myeloid derived suppressor cells (MDSCs). MDSCs are thought to play a critical role in promoting tumor progression by blocking the tumor killing function of cytotoxic T cells in the tumor microenvironment (TME). Our studies revealed all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized murine models of non-small cell lung cancer (NSCLC) with LKB1 and KRAS co-mutations to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T cell proliferation and generated systemic tumor-specific immunity. We observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models. We demonstrated that ATRA suppresses tumor growth through the inhibition of immunosuppressive MDSCs in the TME, and preliminary data indicates that ATRA increases intracellular reactive oxygen species (ROS) and IFN signaling in MDSC. Our findings implicate MDSCs as a potential mediator of immunosuppression in Lkb1-deficient NSCLC and provide a rationale for utilizing ATRA in combination with anti-PD-1 therapy in patients with Lkb1-deficient NSCLC refractory to ICIs. * B. Liu and S. M. Dubinett contributed equally to this work Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen W. Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Camelia Dumitras, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Bin Liu, Steven M. Dubinett. ATRA mediated inhibition of myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in murine models of LKB1-deficient non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2124.
Metastatic Rhabdomyosarcoma: Results of the European <i>Paediatric</i> Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study
Authors: Reineke A. Schoot, Julia C. Chisholm, Michela Casanova, Veronique Minard-Colin, Birgit Geoerger, Alison L. Cameron, Beatrice Coppadoro, Ilaria Zanetti, Daniel Orbach, Anna Kelsey, Timothy Rogers, Cecile Guizani, Markus Elze, Myriam Ben-Arush, Kieran McHugh, Rick R. van Rijn, Sima Ferman, Soledad Gallego, Andrea Ferrari, Meriel Jenney, Gianni Bisogno, Johannes H.M. Merks
Journal: Journal of Clinical Oncology (2022)

Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
Abstract 4050: Effect of benzofuran pharmacophores on CYP-activated duocarmycin bioprecursors
Authors: Zoe H. Jukes
Journal: Cancer Research (2022)

Abstract Duocarmycins are natural DNA alkylators which have potent toxicity with no established mechanism of resistance. Prodrug versions need to be developed to ensure a sufficient therapeutic window for cancer treatment (1). A series of duocarmycin bioprecursors have been developed in-house which lack a key hydroxyl trigger group, required for spirocyclisation and subsequent activation. This hydroxyl group can be regioselectivity restored by specific Cytochrome P450 enzymes (CYPs), with a primary focus on cancer associated isoforms CYP1A1 and CYP2W1 (2). An exploratory library of analogues of our lead compound, ICT2700 (CYP1A1 and CYP2W1 activated), has been synthesized and elucidated aspects of the structure-activity relationship (SAR) between the compound and subsequent toxicity in CYP transfected and mock cell lines, using MTT assays. The data shows the importance of having an indole in the DNA recognition subunit (the non-alkylating subunit) for CYP1A1 and CYP2W1 activation. Further, a compound with thus far unexplained activity was identified. ICT11038 has a benzofuran instead of an indole in the recognition subunit and subsequently demonstrates inherent nanomolar toxicity consistently in all cell lines tested, including a range of cancerous and non-cancerous cells, which is not dependent on cytochrome expression. CYP1A1 has been shown to enhance the toxicity of ICT11038 further but is not required for nanomolar toxicity. Further SAR exploration and western blots confirm that the inherent toxicity is achieved through DNA damage despite lacking the key trigger group, suggesting a novel activation pathway. Additionally, our SAR studies show that replacing the indole of the DNA alkylation subunit with a benzofuran ablates CYP dependent activity, with one exception, ICT2724. ICT2724 is non-toxic in mock transfected cells but is toxic in CYP1A1 transfected cells, albeit it at higher concentration than ICT2700. ICT2724 is analogous to ICT2700, except for the direct indole to benzofuran substitution. Other compounds with benzofurans in the alkylating subunit compounds are not metabolized to a toxic compound by CYP1A1 or CYP2W1 despite their indole equivalents being good prodrug candidates. To conclude, the introduction of the benzofuran functional group into the CYP-activated duocarmycin bioprecursor pharmacophores produces an unexplained pattern of CYP activation and, in one example, an intrinsically toxic DNA damaging agent (ZYP-11038). References (1) Z. Jukes et al, Drug Discov Today, 2020, 26(2), 577-584, https://doi.org/10.1016/j.drudis.2020.11.020 (2) H. Sheldrake et al, J. Med. Chem, 2013, 56(16); 6273-6277, dx.doi.org/10.1021/jm4000209 Citation Format: Zoe H. Jukes. Effect of benzofuran pharmacophores on CYP-activated duocarmycin bioprecursors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4050.
Trends and Risk Factors Associated With Stroke Recurrence in China, 2007-2018
Authors: Jie Xu, Xing Zhang, Aoming Jin, Yuesong Pan, Zixiao Li, Xia Meng, Yongjun Wang
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Recurrent stroke rates have decreased substantially in Western countries. However, data on changes in stroke recurrence and risk factor patterns in China are limited. <h3>Objective</h3> To systematically assess stroke recurrence trends by evaluating temporal improvement in guideline-recommended secondary prevention treatment performance and changes in risk factor patterns over 10 years in China. <h3>Design, Setting, and Participants</h3> This post hoc cohort study was conducted based on data from the China National Stroke Registries (CNSRs, comprising 3 phases, I-III, from 2007-2018). Participants were patients with ischemic stroke who were enrolled in CNSR I or III within 7 days of symptom onset. Data were analyzed from September through November 2021. <h3>Exposures</h3> Vascular risk factors included current smoking, alcohol consumption, hypertension, diabetes, coronary artery disease, atrial fibrillation, and low-density lipoprotein cholesterol (LDL-C) levels. <h3>Main Outcomes and Measures</h3> The cumulative incidence rates of stroke recurrence at 3, 6, and 12 months were calculated, and the performance of guideline-based secondary prevention treatments was investigated at each visit in CNSR I (2007-2008) and III (2015-2018). Logistic regression models were used to evaluate changes in risk factor patterns for stroke recurrence based on data from CNSR I and III. <h3>Results</h3> A total of 10 952 patients with ischemic stroke from CNSR I (6740 [61.5%] men; median [IQR] age, 67 [57-75] years) and 10 348 patients with ischemic stroke from CNSR III (7128 [68.9%] men; median [IQR] age, 63 [54-70] years) were selected. Over 10 years, the adjusted cumulative incidence of recurrent stroke within 12 months decreased from 15.5% (95% CI, 14.8%-16.2%) to 12.5% (95% CI, 11.9%-13.1%) (P &lt; .001). Factors associated with increased risk of stroke in CNSR I that were still associated after 10 years included age per 10 years (CNSR I: odds ratio [OR], 1.24; 95% CI, 1.18-1.31; CNSR III: OR, 1.08; 95% CI, 1.01-1.15), prior stroke (CNSR I: OR, 1.62; 95% CI, 1.45-1.82; CNSR III: OR, 1.66; 95% CI, 1.44-1.92), coronary heart disease (CNSR I: OR, 1.21; 95% CI, 1.04-1.40; CNSR III: OR, 1.23; 95% CI, 1.02-1.49), and LDL-C level per 10 mg/dL (0.259 mmol/L) (CNSR I: OR, 1.02; 95% CI, 1.01-1.04; CNSR III: OR, 1.02; 95% CI, 1.00-1.03), whereas atrial fibrillation (CNSR I: OR, 1.51; 95% CI, 1.26-1.81; CNSR III: OR, 0.95; 95% CI, 0.74-1.23) was no longer an independent risk factor in 2015 to 2018. <h3>Conclusions and Relevance</h3> This study found that stroke recurrence rate in China decreased significantly, but approximately 12.5% of patients still experienced stroke recurrence within 12 months. These findings suggest that more intensive control of traditional risk factors, including LDL-C levels, may be needed to further reduce stroke recurrence.
Abstract 1795: Molecular vulnerabilities of the polyaneuploid cancer cell state
Authors: Luke Loftus
Journal: Cancer Research (2022)

Abstract Once cancer has metastasized it remains incurable owing to resistance to nearly all systemic therapies. Classical views of therapeutic resistance include tumor heterogeneity and genetic instability, but our group and others have identified an unappreciated cancer cell phenotype, the polyaneuploid cancer cell (PACC) state, that provides an alternative model. The PACC state is induced upon exposure to a variety of applied stressors, including multiple different classes of chemotherapy, and is characterized by an enlarged cell size, polyploidy of the typically aneuploid cancer genome, and the ability to repopulate tissue through depolyploidization. We have demonstrated that PACCs are present in a variety of cell lines, arise in response to a multitude of stressors in vitro, and are resistant to cisplatin, docetaxel and Ipatasertib treatment. Thus, we hypothesize that the PACC state is driving cancer’s therapeutic resistance to nearly all available treatment regimens and enabling cancer relapse. Elimination of the PACC state is essential to prevent cancer recurrence, and ultimately enable a cure for cancer.To identify candidate drug targets specific to the PACC state, we performed RNA sequencing, NanoString mRNA panels, bulk proteomics and cell surface proteomics of PACCs versus their parental cell line. PACCs were induced from prostate cancer lines PC3 and LNCaP, and breast cancer line MDAMB231 with both cisplatin and docetaxel treatment. Initial datasets with PC3 cells found that 1013 genes are enriched (greater than 1.5 Log2 Fold Change) in cisplatin induced PACCs while 88 genes are enriched in docetaxel induced PACCs. 22 genes were enriched with both chemotherapy treatments implying that there are genes common to the PACC state. NanoString mRNA and proteomic analysis further validated a subset of the overlapping genes, including ATF3, BIRC3, IL6, and NOX5.Our existing data reveals that there are molecular vulnerabilities of the PACC state that can be manipulated for therapeutic elimination. We will further validate candidate genes across numerous stressors and cell lines and then assess the PACC state’s dependence on these pathways through inhibition and engineered cell lines. Information from these studies will directly lead to development of a therapeutic strategy specifically targeting the PACC state, with the intention of eliminating cancer resistance. Citation Format: Luke Loftus. Molecular vulnerabilities of the polyaneuploid cancer cell state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1795.
Abstract 625: Immunophenotyping of TCR and BCR clonotypes
Authors: Alex Chenchik, Mikhail Makhanov, Tianbing Liu, Lester Kobzik
Journal: Cancer Research (2022)

Abstract TCR and BCR repertoire profiling holds great potential for understanding disease mechanisms and for development of new therapeutics in infectious diseases, autoimmunity and in immuno-oncology. However, this potential could be greatly improved by combining information about receptor clonotypes with immunophenotypes of T and B cells. To facilitate these studies, we developed a novel technology for combined profiling of all human TCR and BCR variable regions and phenotypic characterization of immune cells. The developed TCR/BCR immunophenotyping method involves multiplex RT-PCR amplification and sequencing of CDR3 regions of TCR and BCR genes and a set of the most informative T- and B-cell phenotyping genes. Bioinformatic analysis of NGS data allows profiling of TCR/BCR clonotypes, and identification of major immune cell subtypes and their activation status. Data will be presented showing how combined TCR/BCR clonotype analysis combined with targeted expression profiling of immune cells can be applied for large-scale discovery of novel cell typing and activation biomarkers in several immune-responsive model systems. Preliminary studies indicate the assay has unparalleled throughput, sensitivity, and improved cost-effectiveness for high-throughput immunity biomarker discovery applications. Citation Format: Alex Chenchik, Mikhail Makhanov, Tianbing Liu, Lester Kobzik. Immunophenotyping of TCR and BCR clonotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 625.
Abstract 5900: Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes
Authors: Xingyi Guo, Jingni He, Alicia Beeghly-Fadiel, Zhishan Chen, Chen Cao, Xiao-ou Shu, Wei Zheng, Quan Long
Journal: Cancer Research (2022)

Abstract Transcriptome-wide association studies (TWAS) have been successful in uncovering large numbers of putative disease susceptibility genes. TWAS approaches such as S-PrediXcan, FUSION and TIGAR, show comparable overall performance for susceptibility gene discovery; however, integrating prior disease-specific regulatory information is lacking. To improve accuracy of gene expression prediction by integrating information on susceptible transcription factor (sTF) occupancy in target cells and tissues, we developed an analytical framework, called sTF-TWAS. We evaluated six sets of putative regulatory variants selected from sTF-occupied sites, and performed generalized Berk-Jones (GBJ) analysis to combine sets and quantify overall associations. We demonstrated that sTF-TWAS outperforms S-PrediXcan in both simulation and real data analyses. Using summary statistics data from the Breast Cancer Association Consortium (BCAC), we also incorporated alternative splicing (sp) data in TF-TWAS and identified 76 and 88 significant genes for breast cancer risk at a Bonferroni-corrected P &amp;lt;0.05 from sTF-TWAS and sp-sTF-TWAS, respectively. Of 153 putative susceptibility genes from both sTF-TWAS and sp-sTF-TWAS, 14 genes in 12 loci had novel associations with breast cancer risk and 90 genes were previously unreported by breast cancer GWAS. We also provide strong evidence for 15 previously unreported genes, including 11 essential for breast cell proliferation and five suggested cancer predisposition or driver genes: RAD50, IGHMBP2, ATXN3, KANSL1, and IL6ST. Overall, we demonstrated that our approach has significant advantages over regular TWAS and our findings provide additional insights into the genetic susceptibility of breast cancer. Citation Format: Xingyi Guo, Jingni He, Alicia Beeghly-Fadiel, Zhishan Chen, Chen Cao, Xiao-ou Shu, Wei Zheng, Quan Long. Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5900.
Abstract 4035: Driver-gene dependencies reveal clinically actionable drug repositioning opportunities
Authors: Tomas Babak, Michael Vermeulen, Doris Coto Villa, Andrew Craig
Journal: Cancer Research (2022)

Abstract Cancer cell lines have numerous characteristics that make them favorable pre-clinical research models, yet they are notoriously poor at predicting drug response in the clinic. Here we sought to investigate the utility of synthetic lethality (SL) interactions discovered from large-scale CRISPR functional screens (i.e. the BROAD and Sanger Cancer Dependency Maps or "DepMap") as predictors of targets that validate in patients. Mutual exclusivity, the phenomenon where two genes are rarely mutated together in the same tumor, is a powerful clinical-stage readout that can be caused by synthetic lethality. We found that SL interactions discovered in DepMap are significantly more likely to be mutually exclusive in TCGA when they include a driver (tumor-suppressor/oncogene). These SL interactions represent high-value targeting opportunities with the advantage of clear patient selection criteria based on their driver mutation status. In an effort to identify drugs that target these proteins as potential repurposing opportunities, we found that pharmacogenomic inhibition rarely invokes the same target dependencies as a genetic deletion of the drug target. Nonetheless, we identified several dozen "clean" drugs with potential for repositioning and validated the top candidates in PDx. Although tumours are more heterogenous than cancer cell lines, we show that cell line viability readouts linked to single-gene/drug perturbations can yield accurate predictions of clinical efficacy when tied to tumor-driver biology. Citation Format: Tomas Babak, Michael Vermeulen, Doris Coto Villa, Andrew Craig. Driver-gene dependencies reveal clinically actionable drug repositioning opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4035.
Abstract 2262: Associations of plasma carotenes with lung cancer risk in a low-income population in the southeastern united states
Authors: Yan Sun, Jie Wu, Hyung-Suk Yoon, Wei Zheng, Hui Cai, Maciej S. Buchowski, Adrian A. Franke, William J. Blot, Xiao-ou Shu, Qiuyin Cai
Journal: Cancer Research (2022)

Abstract Lung cancer is the second most common cancer and the leading cause of death from cancer in the U.S. Carotenes, with the properties of antioxidation and immunoregulation, have been demonstrated to have anti-carcinogenic effects. Previous prospective studies showed inverse associations of circulating α-carotene and β-carotene with lung cancer risk among European descendants and Asians. The associations of α-carotene and β-carotene isomers with lung cancer risk have not been investigated, particularly among African Americans (AAs) and low-income populations. We conducted a case-control study including 225 incident lung cancer cases and 429 controls, individually matched on age, race, and sex, nested in the Southern Community Cohort Study, including ~86,000 participants, two-thirds of whom are AAs. Carotene plasma concentrations were determined by a validated assay using high-pressure liquid chromatography with photo-diode array detection. Plasma trans-β-carotene (ORT3 VS. T1=0.54; 95% CI: 0.32-0.90; Ptrend=0.03), cis-β-carotene (ORT3 VS. T1=0.55; 95% CI: 0.32-0.93; Ptrend=0.03), and total β-carotene (ORT3 VS. T1=0.50; 95% CI: 0.30-0.84; Ptrend=0.01) were inversely associated with lung cancer risk. The associations remained significant after excluding cases diagnosed within the first year of follow-up. The inverse associations of plasma cis-β-carotene and total β-carotene with lung cancer risk were only observed among AAs and males. Plasma trans-α-carotene, trans-β-carotene, cis-β-carotene, and total β-carotene were inversely associated with lung cancer risk among those with lower body mass index (&amp;lt;median). In summary, plasma levels of β-carotenes were inversely associated with lung cancer risk in AA and low-income populations. Further studies with a larger sample size are warranted to confirm our findings. Citation Format: Yan Sun, Jie Wu, Hyung-Suk Yoon, Wei Zheng, Hui Cai, Maciej S. Buchowski, Adrian A. Franke, William J. Blot, Xiao-ou Shu, Qiuyin Cai. Associations of plasma carotenes with lung cancer risk in a low-income population in the southeastern united states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2262.